Strategies to Enhance the Hepatitis C Care Cascade Among People Who Inject Drugs

Strategies to Enhance the Hepatitis C Care Cascade Among People Who Inject Drugs Jason Grebely, PhD Associate Professor Viral Hepatitis Clinical Research Program The Kirby Institute UNSW Australia

Disclosures Consultant/advisor for and has received research grants from AbbVie, Bristol-Myers Squibb, Gilead Sciences and Merck/MSD

Strategies to Enhance the HCV Care Cascade Among PWID Issues The burden of HCV infection is growing, including among PWID HCV treatment is effective among PWID HCV testing, assessment and treatment uptake remain low Simple, tolerable, effective therapies are a game changer Strategies to enhance HCV testing/treatment among PWID Treatment as prevention

Defining populations of PWID L I F E T I M E P W I D C U R R E N T P W I D P W I D I N O S T 1) Larney S, et al. Int J Drug Policy 2015. 2) Grebely J et al. Int J Drug Policy 2015.

The HCV care cascade 1) Grebely J et al. Int J Drug Policy 2015.

Enhancing HCV testing and diagnosis of active infection 1) Grebely J et al. Int J Drug Policy 2015.

Successful strategies to increase HCV testing/diagnosis Targeted case-finding 2 Risk-based assessment 3,4 Hepatitis Care Coordination with case management 5 Free counseling and testing 6 Dried blood spot testing 7 Point-of-care testing 6 1) Meyer J, Int J Drug Policy 2015. 2) Cullen B Am J Pub Health 2012. 3) Drainoni M. Am J Pub Health 2012. 4) Litwin A Dig Dis Sci 2012. 5) Masson C, Am J Pub Health 2013. 6) Morano J, J Comm Health 2014. 7) Coats J, Int J Drug Pol 2015.

Successful strategies to increase HCV testing/diagnosis Targeted case-finding 2 Risk-based assessment 3,4 Hepatitis Care Coordination with case management 5 Free counseling and testing 6 Dried blood spot testing 7 Point-of-care testing 6 1) Meyer J, Int J Drug Policy 2015. 2) Cullen B Am J Pub Health 2012. 3) Drainoni M. Am J Pub Health 2012. 4) Litwin A Dig Dis Sci 2012. 5) Masson C, Am J Pub Health 2013. 6) Morano J, J Comm Health 2014. 7) Coats J, Int J Drug Pol 2015.

Assay Analyte Sample Simplification of strategies to increase HCV testing Plasma WB Venepuncture Capillary Drop DBS RNA Core Ag Point of care Centralised

Enhancing diagnoses: DBS in drug services in Scotland

On-line self-collected DBS 1. Order online 2. DBS kit delivered 3. Self sample 4. Post to lab 9. Referral to care 8. Phone call + 7. Reactive? 5. Central lab test HIV testing in comparison with STI clinics (UK) Equal recruitment, return results, and reactivity DBS covered broader geographic area Diagnosed higher number of African American heterosexual men Terrence Higgins Trust. Public Health England. 56 Dean St.

Enhancing diagnoses: POC testing Mobile medical clinic (n=1345) Accepted HCV testing N=438 (33%) 48% selected POC testing 52% selected phlebotomy 94% linked to HCV care 18% linked to HCV care P<0.001 Morano J, J Comm Health 2014.

Enhancing diagnoses: POC HCV RNA testing GeneXpert PCR-based portable system Test results in 100 min RNA confirmation in one visit 1) Cepheid. Product Information.

GeneXpert (Cepheid) POC test for HCV Minivette capillary tube Xpert machine Laptop Finger-prick Single-use test cartridge Xpert cartridge

Diagnostic models of care Sexual health Drug and alcohol clinics NSP services Community health centres Clinics Small labs Primary health care / GPs Prisons Central lab Centralised Decentralised

Cohn et al. 2015. Curr Opinio. Simplified diagnostic monitoring for hepatitis C in the new era of directly acting antivirals. Simplified monitoring Treatment Viral recurrence <12 weeks Treatment 4wk 8wk EOT SVR12 SVR24 Current HCV diagnostics Ab Gt VL Fibrosis VL VL VL VL Simplified diagnostics Qual RNA +Fibrosis Qual RNA Self collected DBS kit

Enhancing linkage to care and liver disease assessment 1) Grebely J et al. Int J Drug Policy 2015.

Enhancing linkage to care: FibroScan -based screening/assessment www.liverlife.org.au Social marketing to inform campaign resources Implementation phase: four clinics; one day per week for four weeks (with peer-based support), with subsequent clinical follow-up 95% reported that FibroScan was acceptable 60% returned for post-fibroscan assessment by a nurse/specialist Marshall A, et al. Int J Drug Policy 2015.

Enhancing linkage to care: Hepatitis care coordination RCT of participants attending OST clinics (n=489) Intervention arm received on-site screening, enhanced education and counseling, and case management services Those receiving intervention more likely to be linked to care 6-months post-follow-up (OR = 4.10; 95% CI = 2.35, 7.17) Masson C, et al. Am J Pub Health 2013.

Enhancing linkage to care: Multiple models of HCV care One size does not fit all Drug and alcohol clinics Primary health care/gp centres Tertiary care M o d e l s o f H C V C a r e Prisons Harm reduction drop-in centres Community health centre Bruggmann P and Litwin A Clinical Infectious Diseases 2013.

Enhancing HCV treatment and cure 1) Grebely J et al. Int J Drug Policy 2015.

Treatment outcomes: History of injecting - PEG-IFN/RBV 56% (95% CI, 51%, 60%) Dimova R, et al Clinical Infectious Diseases 2013

Treatment outcomes: Active injecting - PEG-IFN/RBV 56% (95% CI, 50%, 61%) Aspinall E, et al Clinical Infectious Diseases 2013

EFFICACY 3 years 20 years PEG-IFN/RBV/SOF PEG-IFN/RBV/SMV SOF/SMV SOF/LDV PTV/OBV/DSV/RBV SOF/DCV PEG-IFN/RBV/TVR PEG-IFN/RBV/BOC PEG-IFN/RBV 48 WEEKS 24-48 WEEKS IFN/RBV 24 WEEKS 12 WEEKS IFN TOLERABILITY Dore GJ & Feld J. CID 2015

HCV life cycle: targets for antiviral therapy Polyprotein Translation Protease Inhibitors NUCLEUS Protease Cleavage LDL-R NS5A Inhibitors NS5A Replication Complex SRB 1 CD8 1 RNA Uncoating CLDN1 OCLN Membranous Web Polymerase RNA Inhibitors Replication RdRp + - + Viral Assembly Viral Release Dore and Feld CID 2015

IFN-free Genotype 1 100 90 80 Naïve (12 wks) Exp (12 wks) Naïve (8 wks) 70 SVR12 % 60 50 40 30 20 10 0 SOF/LED PTV/OBV/DSV/RBV GZR/EBR SOF/SMV 26 Zeuzem, NEJM 2014; Afdhal, NEJM 2014; Kowdley, NEJM 2014; Feld, NEJM 2014; Zeuzum, ILC 2015; Kwo, ILC 2015

IFN-free HIV infection GT1, treatment naïve, F0-4; 12 weeks duration 100 90 HCV HIV/HCV 80 70 SVR12 % 60 50 40 30 20 10 0 66/70 54/56 SOF/LED PTV/OBV/DSV/RBV SOF/DCV GZR/EBR Afdhal, NEJM2014; Naggie, CROI2015; Feld, NEJM2014; Rockstroh, WAC2014; Wyles, CROI2015; Zeuzem, ILC2015; Rockstroh, ILC2015; Poordad, ILC2015

IFN-free OST GT1, treatment naïve, F0-4; 12 weeks duration 100 90 80 Non-OST OST 70 SVR12 % 60 50 40 30 20 10 0 66/70 54/56 SOF/LDV PTV/OBV/DSV/RBV GZR/EBR 184/201 28 Afdhal, NEJM 2014; Feld, NEJM 2014; Lalezari, IAC 2015; Zeuzem, ILC 2015; Jacobson, AASLD 2014; Dore AASLD 2015.

IFN-free OST GT1, treatment naïve, F0-4; 12 weeks duration 100 90 80 Non-OST OST 70 SVR12 % 60 50 40 30 20 10 0 66/70 54/56 SOF/LDV PTV/OBV/DSV/RBV GZR/EBR 189/198 29 Afdhal, NEJM 2014; Feld, NEJM 2014; Lalezari, IAC 2015; Zeuzem, ILC 2015; Jacobson, AASLD 2014; Dore AASLD 2015

Elbasvir/Grazoprevir: C-EDGE CO-STAR study Phase 3, randomized, parallel-group, placebo-controlled, double-blind trial Treatment naïve, GT1, 4, 6; mixed genotypes of 1, 4, and 6 allowed On opiate substitution therapy (OST) for at least 3 months and consistently kept at least 80% of scheduled appointments while on OST Goal of 20% with cirrhosis and may be co-infected with HIV Immediate Treatment Arm EBR / GZR, n = 201 Unblinding Follow-up for 24 weeks Deferred Treatment Arm Placebo, n = 100 Unblinding EBR / GZR, n=100 Follow-up for 24 weeks D1 W4 W8 W12 W16 W22 W28 W36 W52 Dore GJ, et al. AASLD 2015.

% SVR12 (95% CI) SVR - Immediate Treatment Group Full analysis set 100 91.5 93.5 93.3 91.7 95.5 80 60 40 20 20.0 0 All GT GT1a* GT1b GT4 GT6 mfas 184/201 144/154 28/30 11/12 1/5 189/198 Relapse 7 4 1 0 2 7 Reinfection 5 3 0 0 2 -- LTFU or discontinued unrelated to VF 5 3 1 1 0 2 (excluded) *Includes one subject with mixed infection (GT1a and GT1b) who achieved SVR12 Includes one subject with HCV RNA>LLoQ consistent with reinfection; this subject was lost to follow-up and did not return for confirmation of HCV RNA; this subject was discontinued for administrative reason and counted as a failure in the FAS, GT = genotype; LTFU = lost to follow-up; VF=virologic failure Dore GJ, et al. AASLD 2015.

% SVR12 (95% CI) SVR - Immediate Treatment Group Modified analysis set 100 95.5 96.1 96.6 100.0 60.0 80 60 40 20 0 All GT GT1a* GT1b GT4 GT6 189/198 147/153 28/29 11/11 3/5 Failures Relapse 7 4 1 0 2 Discontinuation 2 2 0 0 0 Reinfection counted as success 5 3 0 0 2 LTFU or discontinued unrelated to Virologic Failure excluded from mfas analysis 3 1 1 1 0 *Includes one subject with mixed infection (GT1a and GT1b) who achieved SVR12 Dore GJ, et al. AASLD 2015.

Factors associated with SVR12 Dore GJ, et al. AASLD 2015.

% Adherence Adherence to therapy >80% (>67 doses) >90% (>76 doses) >95% (>79 doses) 100 90 80 70 60 50 40 30 20 10 0 100.0 99.0 96.5 100.0 100.0 Immediate treatment arm 100.0 Deferred treatment arm Dore GJ, et al. AASLD 2015.

% Adherence Adherence to therapy across Phase III program >90% (>76 doses) 100 90 80 70 60 50 40 30 20 10 0 99.0 99.5 99.7 CO-STAR (n=201) Co-Infection (n=218) Treatment-Naïve (n=316) Dore GJ, et al. AASLD 2015.

Urinary Drug Screen: baseline and on-treatment 66/70 54/56 184/201 Dore GJ, et al. AASLD 2015.

Adverse events 25 ELB/GZR (n=201) 20 PBO (n=100) 15 10 5 0 66/70 54/56 184/201 Fatigue Headache Nausea Serious AE Discontinue Deaths Dore GJ, et al. AASLD 2015.

Sofosbuvir-based therapy among recent PWID PWID with G1-4 attending OST clinics and receiving sofosbuvir-based regimens with ribavirin or PEG-IFN/ribavirin (n=61) Blister-pack for adherence monitoring 61% with drug use at baseline and 51% with drug use during treatment Overall SVR was 80% (vs. expected of 85%) Litwin A, et al. INHSU 2015, Sydney, Australia.

Restricting HCV treatment access to PWID in the US Barua S, et al Ann Int Med 2015

Sofosbuvir/velpatisvir GT1-6, treatment naïve and exp. (28%), F0-4 (21% F4), 12 wks 100 90 80 SVR12 % 70 60 50 40 30 20 10 0 29/41 11/11 18/30 24/30 5/11 323/328 202/215 66/70 237/238 201/216 264/277 206/216 54/56 116/116 209/214 34/35 211/217 41/41 100/101 31/47 GT1 GT2 GT3 GT4 GT5 GT6 Feld JJ, et al. NEJM 2015; Foster GR, et al. NEJM 2015

Restricting HCV treatment access to PWID in the US AASLD/IDSA HCV treatment guidelines Recent and active IDU should not be seen as an absolute contraindication to HCV therapy. Scale up of HCV treatment in persons who inject drugs is necessary to positively impact the HCV epidemic in the United States and globally. http://www.hcvguidelines.org/

Recommendations for HCV management in PWID Grebely, et al. Int J Drug Policy. 2015

Restricting HCV treatment access in the US Liver disease stage Barua S, et al Ann Int Med 2015

Australia one of the first countries to make access for all public health policy May 2015: Access for all to highly effective HCV treatment a priority Dec 20, 2015: $1 billion for HCV treatment over 5 years (2016-2020)

Adherence to therapy is key.. Litwin A, et al. INHSU 2015, Sydney, Australia.

Enhancing treatment and cure: Adherence

% HCV reinfections after 5 years Education about reinfection risk is crucial 25 Low-risk 24 studies n=6,046 Avg. FU=4.1 years PWID / prisoners 16 studies n=1,203 Avg. FU=5.0 years HIV co-infected 10 studies n=1,106 Avg. FU=3.1 years 24% 20 15 10 8% 5 1% 0 Simmons CID 2016 Low risk PWID / prisoner HIV co-infected

Can HCV treatment play a role in prevention? Martin N, et al. Hepatology 2013.

Can HCV treatment play a role in prevention? Melbourne Martin N, et al. Hepatology 2013 In Press.

Settings for HCV TasP Community-based PWID 88K 50K 24K PWID with Chronic HCV Grebely J and Dore GJ Antiviral Research 2014.

Settings for HCV TasP Drug and alcohol 88K 50K 12K 24K PWID with Chronic HCV PWID on OST Grebely J and Dore GJ Antiviral Research 2014.

Settings for HCV TasP Prisons 88K 10K 50K 12K 24K PWID with Chronic HCV PWID on OST Prisoners (per year) Grebely J and Dore GJ Antiviral Research 2014.

Nurse-led model of care Clinical Nurse Consultants Post-test counselling: chronic HCV Protocol-driven investigations Focused history & examination Triage decision Specialist Category A: Discussion & Rx prescription Category B: Teleconference with patient & Rx prescription Category C: Face-to-face review & Rx prescription Clinical Nurse Consultants Treatment Lloyd A et al. Clinical Infectious Diseases 2013

OCT 2014 2019 Prison-based HCV TasP for PWID Primary Objective To evaluate the impact of a rapid scale-up of IFN-free HCV treatment on HCV transmission Primary Endpoint Change in HCV incidence from pre- to post- scale-up of IFN-free HCV treatment ENROLMENT OPEN STUDY CLOSE HCV INCIDENCE AND PREVALENCE SURVEILLANCE INTERFERON-FREE DAA THERAPY 1000-1200 subjects 550+ subjects TRANSLATIONAL RESEARCH

Prison-based HCV TasP for PWID Lithgow Correctional Centre Lithgow Outer Metropolitan Multipurpose Correctional Centre Sydney Dillwynia (Womens) Correctional Centre Sydney Goulburn Correctional Centre Goulburn

Prison-based HCV TasP for PWID HCV incidence and prevalence phase 6-monthly testing and risk behaviour interview (n=359/1,200) Chronic HCV prevalence = 27% Treatment phase DAA therapy for all infected prisoners (sofosbuvir/velpatasvir) Modelling Treatment sample size and epidemiological impact Cost-effectiveness and budget impact Is DAA therapy in prisons good value for money and can we afford it? Qualitative research Patient, provider, staff and policy-maker attitudes & barriers towards DAA therapy Implementation toolkit How can DAA therapy be scaled up across NSW and nationally?

NSP and OST required to optimize TasP Martin NK, et al. Clinical Infectious Diseases 2013.

Lima PLOS ONE 2015 NSP and OST required to optimize TasP

Global NSP coverage is limited Only 41% (n=82) of countries had implemented NSPs Mathers B, et al. Lancet 2010

Secondary Infections Need to scale-up HCV therapy quickly to avert reinfection 250 200 150 100 50 0 3,500 3,000 2,500 2,000 1,500 1,000 500 0 Annual Number Treated Treat 1% Treat 2% Treat 4% Treat 8% Treat 10% Treat 1% Treat 2% Treat 4% Treat 8% Treat 10% Razavi INHSU 2015, Sydney, Australia, Oct 7-9, 2015

HCV test and treat among PWID Increase screening/diagnosis Strategies for enhanced HCV RNA testing (DBS testing and POC RNA) Increase linkage to care and treatment Expanded access to non-invasive tools for staging (Fibroscan) Expanded models of care to engage and treat HCV among PWID Increase treatment response and cure Expanded access to IFN-free therapies among PWID Who will require optimized adherence strategies? Weekly DOT, blister packs, text messaging, mobile apps, etc. Prevention of reinfection Treatment as prevention?

Acknowledgements UNSW Australia Prof. Gregory Dore Prof. Andrew Lloyd Dr. Behzad Hajarizadeh Prof. Carla Treloar Prof. Tony Butler International Collaborators Prof. Alain Litwin (US) A/Prof. Natasha Martin (US) Prof. Peter Vickerman (UK) Prof. Matt Hickman (UK) A/Prof. Viviane Dias Lima (Canada) Prof. Julio Montaner (Canada) Dr. Lynn Taylor (US) Dr. Homie Razavi (US)